Drug-coated balloon

ABSTRACT

Described here are devices, systems, and methods for treating conditions or diseases of the nose, ear, or throat with an expandable device having a drug coating. The expandable devices may be delivered to a body cavity in a low-profile configuration and expanded to contact surrounding tissue. The expandable devices may deliver or release the drug coating to the tissue. Multiple expansions of a single device may be employed during treatment. Various coating excipients and manufacturing parameters for the expandable devices may also be adjusted to enhance or slow transfer of the drug coating and/or release of the drug to the target tissue site. The drug transferred to the tissue may act as an in situ depot that enables maintenance of a therapeutic level of locally delivered drug for a desired time period after removal of the expandable devices.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/004,807, filed on Jan. 22, 2016, now issued as U.S. Pat. No.10,441,757, which claims priority to U.S. Provisional Application Ser.No. 62/106,692, filed on Jan. 22, 2015, and titled ‘DRUG-COATEDBALLOON,” each of which is hereby incorporated by reference in itsentirety.

FIELD

This application is generally related to expandable devices for treatingconditions or diseases associated with bodily structures of the nose,ear, and throat, devices for delivering the expandable devices, andmethods of using them.

BACKGROUND

Rhinosinusitis is a common paranasal sinus condition that is generallyunderstood as encompassing sinusitis and/or rhinitis. Typically,rhinosinusitis is characterized by major symptoms such as nasaldischarge, nasal obstruction, facial congestion, facial pain/pressure,loss of smell, and fever, and minor symptoms such as headache, earpain/pressure, halitosis, dental pain, cough, and fatigue.

Allergic rhinitis is associated with a group of symptoms affecting thenose that occurs when an individual with the condition breaths in anallergen, such as dust, mold, or animal dander. Allergens cause therelease of histamine, which usually causes sneezing, itchy and wateryeyes, runny nose, swelling and inflammation of the nasal passages, anincrease in mucus production, and for some individuals, hives or otherrashes. Allergic rhinitis due to pollen is commonly known as hay fever.

Current treatments for these and other nasal conditions, as well ascertain otic and throat conditions, are primarily pharmaceutical. Drugsin pill form are widely available and easy to take, but can have severaldrawbacks. An orally administered drug may require considerable time towork through the body to become effective, and may have negative sideeffects that can impact the daily life of the patient. Also, the drugmay need to be taken frequently for continued symptom relief. Nasal,otic, and throat topical drug delivery represents an attractivealternative approach for the treatment of local nasal, otic, and throatdiseases. However, current technologies for local drug delivery of drugsin either liquid or powder form, and by spray or direct application, canbe limited by poor patient compliance when repeated doses are required,or poor efficacy due to challenges in delivering a drug to more distalsinus and ear anatomies.

Another challenge with topical drug delivery is presented when the nasalcondition involves treatment of mucosal tissue. Most mucosal epithelialtissues are covered with a glycoprotein rich mucus layer. This mucuslayer is a dynamic layer that generally works to clear contaminants fromthe respiratory system. It typically has a transit and turnover time ofapproximately 15-20 minutes. A locally delivered drug must pass throughthis mucus layer and be taken up by the mucosal epithelium before it ismoved away from the target tissue site.

Accordingly, for certain nasal, otic, and throat conditions, it may bedesirable to treat distal anatomies by distributing high concentrationsof drugs with reduced dosing frequency evenly across treated sites andin the absence of a permanent implant for applications where mechanicalsupport is not necessary. Regarding nasal conditions, it may be usefulto have treatments that can both deliver drugs and dilate target sitessuch as the paranasal sinuses and/or deliver drugs to multiple siteswith a single device. When mucosal tissues are affected, it would bedesirable to have topical treatments where drugs can be delivered andtaken up by tissue before they are cleared from the site by mucociliaryflow.

BRIEF SUMMARY

Described herein are expandable devices coated with a therapeutic agent(drug) that may be physically transferred to the tissue site of interestupon expansion. After therapeutic agent transfer, the expandable devicemay be collapsed and removed. The drug coating may be formulated to betransferred with a single expansion, or when multiple expansions with asingle device are performed, partially transferred with each expansion.The drug coating transferred to the tissue may act as an in situsustained release depot that enables maintenance of a therapeutic levelof locally delivered drug for a desired time frame (e.g., days, weeks,or months). Some variations of the drug coating are formulated for rapiddelivery through the mucous layer of tissue. For example, theseformulations may include one or more mucolytic, mucoadhesive, orpenetration enhancing agents to hasten drug delivery. In othervariations, the expandable device may be combined with an implantabledevice, such as a stent or scaffold.

Described herein is a method of treating a nasal, otic, or throatcondition that may comprise providing an expandable device comprising adrug coating on an external surface thereof and having a low-profileconfiguration and an expanded configuration, delivering the expandabledevice in the low-profile configuration to a target tissue site,expanding the expandable device to the expanded configuration,contacting the tissue treatment site with the expanded expandable devicefor a period of time effective to transfer the drug coating from theexternal surface to the target tissue site, removing the expandablemember from the target tissue site, and maintaining a therapeutic levelof locally delivered drug at the target tissue site from the transferreddrug coating for a time period effective to treat the target tissuesite. The expandable device is typically collapsed prior to its removalfrom the target tissue site.

Some variations of the method include transferring substantially all thedrug coating from the expandable device to the target tissue site with asingle expansion. In other variations, the method includes using asingle expandable device to treat multiple target tissue sites. Forexample, a single expandable device could be used to treat multiplesinuses in a patient. Here the drug coating may be formulated so thatonly a portion of the coating is transferred with each expansion. Thedrug coating may also be configured, e.g., as multiple layers, totransfer one or more drugs over multiple expansions. Various surfacetreatments, e.g., plasma treatment or a hydrophilic primer layer, canalso be applied to the expandable device to manipulate coating transferrates.

The expandable devices may be used to treat inflammation of mucosaltissue, e.g., mucociliary tissue, which is present in the nasal passagesand sinuses, among other structures of the respiratory system. In somevariations, the condition to be treated may be a nasal conditionselected from the group consisting of post-surgical inflammation,rhinosinusitis, and rhinitis, including allergic rhinitis. In suchvariations, the target tissue site may be a paranasal sinus, a sinusostium, an inferior turbinate, a middle turbinate, a superior turbinate,a nasal cavity, the osteomeatal complex, the nasopharynx, adenoidtissue, or a combination thereof. In other variations, the condition tobe treated may be an otic condition selected from the group consistingof post-surgical inflammation, otitis media, Meniere's disease,Eustachian tube dysfunction, and tinnitus. In such variations, thetarget tissue site may be the Eustachian tube, external ear canal, orinner ear. In other variations, the condition to be treated may be athroat condition selected from the group consisting of post-surgicalpain, esophageal cancer, airway stenosis, e.g., tracheal stenosis orsubglottic stenosis, chronic laryngitis, tonsillitis, and epiglottitis.The expandable device may also be employed in methods where it maybeneficial to both dilate and deliver drugs to the target tissue site.

The expandable device may be compliant, semi-compliant, ornon-compliant. Compliant devices may distend upon inflation to theexpanded configuration. The expandable devices may be folded, pleated,or wrapped to achieve a low-profile configuration.

In some variations, the expandable device may be an inflatable balloon.In such variations, the inflatable balloon may have an inflationpressure between about 2 atm and 16 atm. Alternatively, the inflationpressure may be between about 4 atm and 6 atm. In other instances, e.g.,when the inflatable balloon is non-compliant, the inflation pressure maybe at least about 20 atm.

In some variations, the drug coating may comprise a lipophilic drug. Inother variations, the drug coating may comprise a corticosteroid. Whenthe expandable device is used to treat nasal conditions, it may bebeneficial for the drug coating to comprise mometasone furoate.

In some variations, the period of time effective to transfer the drugcoating may be from about 5 seconds to about 2 hours. In othervariations, the period of time effective to transfer the drug coatingmay be from about 10 minutes to about 30 minutes. In yet furthervariations, the period of time effective to transfer the drug coatingmay be from about 30 seconds to about 5 minutes. When multiple sinusesare to be treated, it may be beneficial for the drug coating to betransferred with a 5 second expansion, e.g., a 5 second ballooninflation.

In some variations, the time period effective to treat the target tissuesite may be between 5 days and 90 days. In other variations, the timeperiod effective to treat the target tissue site may be from about 2months to about 3 months. For example, the duration of the treatmentperiod may range from about 7 to about 14 days post balloon dilationonly, about 7 days to about 21 days post balloon dilation only, andabout 28 days post functional endoscopic sinus surgery (FESS) or hybridtreatment.

The drug coating may comprise a drug and an excipient. Multiple drugsand excipients can be included in the drug coating if desired. In somevariations, the drug coating may comprise a drug to excipient ratioranging from about 3:1 to 1:3. For example, the drug to excipient ratiomay be 3:1, 3:2, 1:1, 1:2, or 1:3. For nasal conditions, it may beuseful to include a corticosteroid, e.g., mometasone furoate, as thedrug in the drug coating, as previously stated.

With respect to excipients, the drug coating may comprise at least oneof a poly(ethylene glycol); poly(vinyl pyrrolidone); phospholipids;fatty acids; sodium dodecyl sulfate; polysorbates; pluronics;cyclodextrins such as hydroxypropyl-beta-cyclodextrin; sucrose fattyacid monoester; alkyl glycosides such as decyl maltoside and octylmaltoside; oleic acid; sorbitan trioleate; sorbital; mannitol; pectin;trehalose; tributyl citrate; triethyl citrate; glycerol monooleate;thymol; and shellac. In other variations, the drug coating may compriseat least one of a low molecular weight poly(ethylene glycol), glycerol,fatty acids, sebacates, fatty alcohols, lipids, lecithin, oils such asvegetable oils, glycol esters, and propylene glycol. In othervariations, the drug coating may comprise at least one of a chitosan,collagen, elastin, silk, silk-elastin, alginate, cellulose, cellulosicssuch as hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose, ethylcellulose, dextran, polyalkoanates, hyaluronicacid, gelatin, gellan, carrageenan, polylactide,poly(lactide-co-glycolide), poly(L-lactide-co-caprolactone),polyglycolide, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethyleneglycol), polydioxanone, polyglactin, poly(E-caprolactone),polyglyconate, poly(glycolide-co-trimethylene carbonate), poly(sebacicacid), poly(ester urethane), poly(ester urethane) urea, cross-linkedpoly(ethylene glycol) (PEG), polyNIPAAM, PEG-poly(lactic acid) (PEG-PLA)block copolymers, and poloxamers.

During manufacturing, the expandable device, e.g., a balloon, may becoated with a drug coating formulation by methods such as spray coating,pipette or syringe coating, or dip coating. Spray coating may achieveimproved tissue uptake and drug delivery uniformity. For improvedcoating adhesion, the expandable device may be cleaned with a solventand dried prior to coating. In addition, plasma treatment with an inertgas, such as argon or oxygen, after cleaning may increase the cleaningand wettability of the expandable device surface leading to increasedcoating adhesion and release of the coating upon contact with mucus atthe mucosal tissue site. In some variations, the manufacturing methodmay include cleaning the balloon surface and/or treating the balloonwith plasma, inflating the balloon, spray coating the balloon with adrug coating formulation, drying the balloon coating at room temperatureor elevated temperature, and re-folding the balloon. In othervariations, the manufacturing method may include cleaning the balloonsurface and/or treating the balloon with plasma, inflating the balloon,spray coating the balloon with a drug coating formulation, exposing thecoated balloon to a solvent vapor (solvent vapor annealing), andre-folding the balloon.

Varying the environmental conditions during the drug coating process mayaffect the rate of drug release from the expandable device. Certainconditions may favor crystal or amorphous forms of the drug, which inturn can modify the rate of drug release. In some variations, the drugcoating is exposed to a solvent vapor after application to modify thedrug form in the coating, e.g., to produce more crystalline drug, whichis generally associated with longer release rates. Accordingly, bymanipulating various conditions, drug release can be tailored to theparticular indication and/or anatomy being treated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1L depict exemplary shapes for the expandable device.

FIG. 2 illustrates exemplary processes for coating the expandabledevice.

FIG. 3 is a graph that illustrates the blood plasma concentration ofmometasone furoate after delivery of a drug coating to an ovinemaxillary sinus over a 7 day period.

DETAILED DESCRIPTION

Described here are devices, systems, and methods for treating one ormore conditions with an expandable device. Generally, the systems maycomprise an expandable device sized and configured for placement in oneor more body cavities. The expandable device may be delivered in alow-profile configuration, and may be expanded in the cavity to contacta large surface area of surrounding tissue. The expandable device may beconfigured to deliver or release one or more drugs to the surroundingtissue and then be removed. The device may be expanded once or multipletimes at the same or different treatment sites. Generally, the treatmentmethod may provide therapeutic levels of drug for a desired time periodafter expansion and removal of the expandable device. The methods anddevices may be useful when drug delivery to tissue sites having amucociliary layer, e.g., the paranasal sinuses, is desired.

The expandable device may have several applications. It may be adaptedin size, configuration, and material for different uses, such as in thenose, ear, and throat. The expandable device may be useful in treatingconditions involving mucosal inflammation. In some variations, thedevices, systems, and methods may be used for treating one or more sinusor nasal conditions including, but not limited to rhinitis, allergicrhinitis, acute sinusitis, and chronic sinusitis. In other variations,the systems, and methods may be implemented during a dilation procedure.For example, one or more drugs (e.g., a corticosteroid) may be deliveredto reduce inflammation post ballooning, post dilation, or other surgeryof the sinuses and/or sinus ostia. In other variations, one or moredrugs may be delivered to the sinus and/or sinus ostia for allergysymptom relief. As another example, an expandable device, such as aninflatable balloon, may be used to deliver drugs to the inferiorturbinate for the treatment of allergic rhinitis. Use of a temporaryinflatable balloon for drug delivery may in some cases be advantageousover an implant in the inferior turbinate, since the latter may cause asneezing reflex. As yet another example, it may be used for delivery ofan anti-inflammatory (e.g., a corticosteroid) for reduction ofinflammation post functional ethmoid surgery, including when mechanicalsupport and a permanent implant may not be necessary.

In other variations, the devices, systems, and methods described heremay also be for treating one or more conditions of the ear. For example,an expandable device may deliver drugs to the Eustachian tube postballooning to treat Eustachian tube dysfunction, which may contribute tootitis media or other diseases of the ear. As another example, theexpandable device may be used for drug delivery to the external earcanal for acute otitis media, chronic otitis media or swimmer's ear. Itmay also be used for drug delivery to the middle and/or inner ear forotitis media, Meniere's disease, tinnitus, or other applicable diseases.

In other variations, the expandable device may also have applications inthe throat, where drug delivery may be for post-surgical pain, such astonsillectomy pain, or for esophageal cancer, airway stenosis (e.g.,tracheal stenosis or subglottic stenosis), chronic laryngitis,epiglottitis, other inflammatory diseases, and/or other diseases of thethroat.

Also described here are systems and methods for delivering andmanufacturing the expandable devices described herein. In somevariations, the systems may comprise a delivery device for deliveringthe expandable device into the body.

Devices

Expandable Devices

The expandable devices described herein may generally be movable betweena low-profile configuration and an expanded configuration. Theexpandable devices may comprise a flexible membrane that may beconfigured to provide even and consistent contact with, and substantialcoverage of, the surrounding tissue upon expansion. In some variations,the flexible membrane may comprise a tubular sheath that may be expandedusing a mechanical system coupled to the internal surface of the tubularsheath. In other variations, the flexible membrane may comprise aninflatable structure that may be expanded using a fluid. For example,the inflatable structure may be a balloon, wherein the balloon may beexpanded to an expanded configuration by delivery of a liquid (e.g.,saline) or gas (e.g., air) to the interior of the balloon. In somevariations, the expandable devices may comprise a hub connecting themembrane to a shaft.

The low-profile configuration may be the expandable device in itscollapsed state (or non-inflated state), or the expandable devicepleated, folded, or wrapped upon itself. In some instances, thelow-profile configuration may be the expandable device in a partiallycollapsed (or partially inflated) state. A sheath or other covering maybe used to cover the expandable device. In one variation, a sheath orcover may constrain the expandable device in its low-profileconfiguration. In this variation, the expandable device may beself-expanding. In some variations, expansion to the expandedconfiguration is accomplished via inflation with a fluid or a gas.

The expandable device may be non-compliant, semi-compliant, orcompliant. While the following description relating to compliance isprimarily directed to a balloon, it may apply to expandable devices ofother forms and configurations. Balloon compliance is a term generallyused to describe the degree to which the diameter of a balloon changesas a function of inflation pressure.

In some variations, the expandable device comprises a compliant balloon.Compliant balloons may be made from materials having low (e.g., Shore A)durometer such as polyurethane, polyvinyl chloride (PVC), polyolefins,and other elastomers, and may be capable of increasing their diameter byabout 100% to about 600% as inflation volume of the balloon increases.Compliant balloons typically have an inflation pressure less than about16 atm. The compliant balloons may have any suitable shape, e.g., asshown in FIGS. 1A-1L. In some variations, compliant balloon shapes mayinclude spherical type shapes that may be useful when drug deliverywithout mechanical dilation is needed. It is understood that thecompliant balloons may be configured to have other shapes andgeometries.

Variations of the compliant balloon may generally be low pressure,elastic, and capable of distending significantly (e.g., up to 600%). Insome applications, the compliant balloon may be configured to conform tothe body cavity in which it is expanded in order to contact a largesurface area of the surrounding tissue. The pressure exerted by thecompliant balloon when expanded may be sufficient to maintain contactwith the tissue, but may not cause unwanted damage (e.g., breaking bone,tissue damage) or reshaping (e.g., displacing tissue). To achieve this,the compliant balloon material may comprise, for example, latex,silicone, polyurethane (PE), polyvinyl chloride (PVC), and/or lowdurometer Pebax® polyether block amides. Further, the inflation pressureof the compliant balloon may be, for example, between about 2 atm and 16atm, between about 2 atm and 10 atm, or between about 4 atm and 6 atm.Compliant balloons may be able to conform to irregular geometries inbody cavities in order to effectively deliver drugs, for example, in thenasal or sinus cavities, or sinus ostia. For example, a compliantballoon may be used to contact the inferior turbinate for the treatmentof allergies. In some variations, the compliant balloons may be moldedfrom suitable materials, e.g., the materials described above. To achievea low profile delivery configuration, the compliant balloons may bepleated, folded, or wrapped upon themselves.

Alternatively, the expandable device may comprise a non-compliantballoon. Non-compliant balloons may be made from non-elastic materialshaving higher durometer such as polyethylene terephthalate (PET),crosslinked polyethylene, and nylon polymers. Non-compliant balloons mayhave an inflation pressure between 10 atm and 22 atm, between 14 atm and20 atm, or 20 atm or higher, and may only distend by about 5% to about7%, or about 5% to about 10%, when inflated. The non-compliant balloonsmay have any suitable shape, e.g., as shown in FIGS. 1A-1L. In somevariations, non-compliant balloon shapes may include cylindrical typeshapes. It is understood that the non-compliant balloons may beconfigured to have other shapes and geometries.

The non-compliant balloon may be molded to a desired inflated geometryfrom non-compliant materials that retain their predetermined size andshape under pressure. To achieve a low profile delivery configuration,the non-compliant balloon may be pleated, folded, or wrapped uponitself. Upon inflation, the balloon may unfurl to expand to thepredetermined expanded configuration. The expanded non-compliant balloonmay contact a large surface of the surrounding tissue without dilatingor damaging the tissue.

In a further variation, the expandable device may comprise asemi-compliant balloon. Semi-compliant balloons are generally formed bycompliant materials but have a higher inflation pressure than compliantballoons. For example, semi-compliant balloons may be made frompolyethylene terephthalate (PET), nylon polymers, or Pebax® polyetherblock amides (single or dual layer) but have an inflation pressure of 10atm to 20 atm. Such balloons may be capable of distending about 18% toabout 30% upon inflation. Other semi-compliant balloons may allow forabout 5% to about 10% distension, and may have an inflation pressurebetween about 8 atm to 15 atm, more specifically between about 10 atm to12 atm. Semi-compliant balloons may both distend with inflation andunfurl with inflation. Semi-compliant and non-compliant balloons may beuseful when enlargement or dilation of tissue sites, e.g., sinus ostia,is needed.

Semi-compliant balloons may have any suitable shape, e.g., as shown inFIGS. 1A-1L. It is understood that the semi-compliant balloons may beconfigured to have other shapes and geometries. In some variations, thesemi-compliant balloons may be molded from suitable materials, e.g., thematerials described above. To achieve a low profile deliveryconfiguration, the semi-compliant balloons may be pleated, folded, orwrapped upon themselves.

Balloon sizes and shapes may be designed for specific anatomies andapplications. While compliant balloons may conform to the particulargeometries of a cavity, the balloon may additionally or alternatively bemolded to match the general size and shape of the space. For example,cylindrical compliant balloons having sizes of, for example, 3 mmdiameter×20 mm length, may be utilized for Eustachian tube treatment(i.e., to treat the cartilaginous portion of the tube). Sphericalnon-compliant balloons having a diameter of, for example, about 15 mm toabout 50 mm, may be used for treatment of the inferior turbinate. Whentreatment of the sinus ostium is desired, balloons having a diameter ofabout 4 mm to about 6 mm, and a length or about 10 mm to about 25 mm,may be employed. Shorter lengths may be utilized for pediatric patients.Molding the size and shape of a non-compliant balloon may require moretailoring to the deployment location (i.e., cavity) so that the balloonmay amply contact the surrounding tissue upon inflation (without theability to conform to the tissue) without dilatation. In somevariations, the balloons may comprise a multi-lobe shape, where thelobes may have the same or different shapes.

Referring to FIGS. 1A-1L, the compliant, non-compliant, andsemi-compliant balloons may be conical (FIG. 1A), tapered (FIG. 1J),spherical (FIG. 1B), square (FIG. 1G), a square with a conical end (FIG.1H), an elongated square with a conical end (FIG. 1C), an elongatedsphere (FIG. 1D), an elongated sphere with a conical end (FIG. 1I), ordog-bone shaped (FIG. 1E). Alternatively, the balloons may comprise astep or multiple steps of varying height (FIG. 1K), or may be configuredto expand in a particular direction (FIGS. 1F and 1L). Directionallyexpanding balloons may be useful e.g., when it is desired to deliverdrug to the inferior turbinate but not the nasal septum. Another usefulballoon shape may be similar to a star.

Additionally, the balloons may include one or more ports configured forsuction, irrigation, deployment of viewing elements (e.g., opticviewers, magnetic imagers, etc.), and/or use with an endoscope orrhinoscope. The balloons may be delivered over a guidewire, withfiberoptic guidance, or via a conformable shaft. In some variations, theballoons may be configured to be delivered by a physician using a singlehand. To achieve a low-profile delivery configuration, the compliant,non-compliant, and semi-compliant balloons may be pleated, folded, orwrapped upon themselves.

Drug Coating

In some variations, the expandable device may be configured to releaseone or more drugs therefrom. The drug may be part of a coating on theouter surface of the expandable device. In addition to the drug, thecoating may also include an excipient or combination of excipients.Suitable excipients include without limitation, poly(vinyl pyrrolidone),polysorbates, poly(ethylene glycol), propylene glycol, glycerolcaproate, and combinations and mixtures thereof.

The drug coating may cover the entire expandable device or a portionthereof. For example, the drug coating may be patterned on theexpandable device or provided on specific areas of the expandabledevice, depending on, e.g., the anatomy to be treated. For example, thepattern could include solid or dashed lines of the drug coating, thedrug coating dotted on the expandable device, or the drug coatingprovided as a spiral around the expandable device, etc. The thickness ofthe drug coating may range from about 10 μm to about 500 μm. In somevariations, the thickness of the drug coating can be varied, e.g.,structured to be thicker on some areas of the expandable device thanothers. The drug coating may be formulated to have a similar complianceas the expandable device, with an appropriate ductility to preventbreaking and flaking upon distension or unfolding of the expandabledevice. In addition to the drug, the coating formulation may includeother compounds or additives, such as excipients, binding agents,plasticizers, solvents, surfactants, chelators, penetration enhancers,mucoadhesives, mucolytics, and the like. When the site to be treatedincludes mucosal or mucociliary tissue, it may be useful for the drugcoating to include excipients such as a penetration enhancer, amucoadhesive and/or a mucolytic to enhance drug delivery across themucus layer. In some variations, excipients having a molecular weight of1000 or less may be beneficial in enhancing drug uptake through mucosaltissue.

Another coating (e.g., a topcoat) may be applied on the drug coating toprotect it prior to deployment of the expandable device or to facilitaterelease of the drug (e.g., by priming the surface of the expandabledevice with a hydrophilic priming agent, or by including a hydrophilicpriming agent in the topcoat). The topcoat may lack an active agent, butin some instances it may include small amounts of one or more activeagents. In some variations, the topcoat is configured to dissolve ordegrade upon contact with the target tissue site but before theexpandable device is expanded.

The coating formulation may comprise an excipient to plasticize thecoating and/or enhance film integrity. An optional plasticizer may beadded to increase ductility and integrity of the coating. Examples ofplasticizers may include low molecular weight poly(ethylene glycol),glycerol, polysorbates, fatty acids, sebacates, fatty alcohols, lipids,lecithin, oils such as vegetable oils, glycol esters, propylene glycol,and castor oil.

An excipient or polymer may be added to the coating formulation toenhance film forming and coating integrity. These materials may benatural or synthetic. Natural polymers may include chitosan, collagen,elastin, silk, silk-elastin, alginate, cellulose, dextran,polyalkoanates, hyaluronic acid, gelatin, and gellan. Syntheticbioresorbable polymers may include polylactide (PLA),poly(lactide-co-glycolide), poly(L-lactide-co-ε-caprolactone),polyglycolide, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethyleneglycol) (PEG), polydioxanone, polyglactin, poly(ε-caprolactone),polyglyconate, poly(glycolide-co-trimethylene carbonate), poly(sebacicacid), poly(ester urethane) and poly(ester urethane) urea.

When PEG is used, its molecular weight may be adjusted to improvecoating properties. In general, the molecular weight of PEG ranges fromabout 5 kDa to about 10 kDa. In some variations, low molecular weightPEG (e.g., less than about 1.2 kDa) may enhance the rate of drug releaseand mucosal tissue uptake. In other variations, high molecular weightPEG (e.g., more than about 1.2 kDa) may slow the drug release rate overmultiple inflations or delay mucosal tissue uptake. Alternatively, thecoating can include layers of PEG having different molecular weights.For example, layers could alternately include high and low molecularweight PEG when multiple inflations are being contemplated.

Cross-linked versions of synthetic coating excipients may also be usedand include without limitation, crosslinked PEG, polyNIPAAM, PEG-PLAblock copolymers, and thermally cross-linked polaxamers (e.g.,Pluronics). Crosslinked PEGs may consist of pre-reacted reactive PEGssuch as mixtures of reactive multi-arm PEG succinimydyl succinate andmulti-arm PEG amine. Either 4-arm PEG or 8-arm PEG may be utilized tocontrol the crosslink density and swell ratio. Other multi-arm PEG-NHS(N-hydroxylsuccinimide) esters such as PEG succinimidyl glutarate may beused. Cellulosics may also be added to the coating formulation.

The formulation may also comprise an excipient for enhancing or slowingcoating transfer, enhancing or slowing drug release from the coating,and/or enhancing adhesion to tissue. Particular combinations ofexcipients and drugs may help to allow the coating to be released fromthe outer membrane of the expandable device and to adhere to mucusand/or mucosal tissue. Excipients having mucoadhesive properties may beuseful and include without limitation, chitosan, polyacrylic acid,polyglutamic acid, carboxymethylcellulose, sodium hyaluronate, andsodium alginate. In some variations, the coating is formulated to behydrophobic to prevent washout during procedures where tissue sitesundergo irrigation.

Specifically, in some instances, it may be desirable for the drug toexcipient ratio to be high to enhance fast release of drug from theexpandable device during a short time period of inflation. Examplesinclude drug to excipient ratios of 1:3 or higher, or 1:1 or higher. Insome instances, moisture and/or mucous from the body cavity afterdelivery may soften the coating and help to allow the coating to betransferred to tissue. In other instances, the excipient may beamphiphilic (i.e., possess both hydrophilic and lipophilic properties)to promote hydrophilic release from the expandable device when moist andlipophilic interaction with the drug. Examples of amphiphilic polymersand excipients may include poly(ethylene glycol), poly(vinylpyrrolidone), phospholipids, fatty acids, sodium dodecyl sulfate,polysorbates, poloxamers, hydroxypropyl-beta-cyclodextrin, and sucrosefatty acid monoester.

Alternatively, the drug to excipient ratio may be adjusted to retard orslow the release of drug to a tissue site. Here higher lipophilic drugto hydrophilic excipient ratios, e.g., ratios of 1:1, 2:1, or 3:1, maybe used to slow dissolution of the drug, and thus slow release. Theseratios may be useful when a single device will be used to treat multiplesites and/or undergo multiple expansions.

Additionally or alternatively, the drug itself may be lipophilic. Inthese variations, if the expanded expandable device presses against andconforms to the tissue at the treatment site, the lipophilic nature ofthe drug(s) contained in the coating on the outside surface of theexpandable device may promote transfer to and absorption by the tissue.Moisture within the body cavity (e.g., the sinus, Eustachian tube andother applicable bodily structures described herein) may facilitate thistransfer. Other factors that may affect drug transfer from theexpandable device (e.g., the balloon) include the amount of contactpressure exerted by the expandable device, the amount of contact of theexpandable device to the tissue site, and the amount of injury to thesurface of the tissue site. The physician may also irrigate the tissueand/or expandable device prior to device deployment to enhance drugrelease from the device.

Once the coating is transferred to tissue, e.g., mucosal tissue, withina body cavity, it may act as an in situ depot that enables maintenanceof a therapeutic local level of drug for a desired time frame. In someinstances, the coating containing the one or more drugs may be at leastpartially biodegradable and/or biosoluble. As the drug and/or coatingdegrades and/or dissolves over the course of the desired time frame, thedrugs may be released to the target tissue and to the anatomies distalto the target tissue. In some variations, the use of cross-linkedcoating excipients may help maintain the drug at the target tissue sitefor the desired time frame. In other variations, the inclusion of highmolecular weight excipients in the coating may enhance residence time ofthe drug at the target tissue site. In yet further variations,incorporating the crystal form of the drug in the coating may help toincrease the efficiency of drug delivery at the target tissue site.

In some instances, use of a non-compliant or semi-compliant balloon(versus a compliant balloon) may increase the efficiency of drug uptakeat a mucosal tissue site. This is because the higher pressures requiredto inflate the balloons may displace the mucous layer and also lead toepithelial tissue injury, which in turn may enhance drug delivery intothe tissue. Tissue injury may also be induced by employing a balloonhaving spikes or a rough surface molded or adhered thereto, or a ballooncapable of scoring, cutting, and/or tearing tissue.

In other instances, use of a mucoadhesive excipient may increase theefficiency of drug delivery at the tissue site. Exemplary mucoadhesiveexcipients include without limitation, carbomers, glyceryl monooleate,hypromellose, oleic acid, polycarbophil, polyethylene oxide,poly(ethylene glycol), and sodium alginate. Other mucoadhesives couldobtain their adhesive properties by wetting of a soluble coating orpolymer, charge adhesion (e.g., of anionic polymers such as polyacrylicacid, cellulosics, chitosan, gellan, carbopol, etc.), and covalentadhesion with e.g., a protein reactive gel such as PEG-NHS. In onevariation, the mucoadhesive is poly(ethylene glycol).

Penetration enhancers may also be included in the coating formulation toenhance drug delivery through, e.g., the mucous layer, and to the tissuesite. Exemplary penetration enhancers include, but are not limited to,dimethyl sulfoxide, glyceryl monooleate, glycofurol, isopropylmyristate, isopropyl palmitate, lanolin, light mineral oil, linoleicacid, menthol, myristic acid, myristyl alcohol, oleic acid, oleylalcohol, palmitic acid, polyoxyethylene alkyl ethers,polyoxylglycerides, pyrrolidone, sodium lauryl sulfate, thymol,tricaprylin, triolein, and combinations and mixtures thereof.

The expandable device may comprise any suitable drug or agent, dependingon the desired use of the device. The drug or agent may comprise atleast one of a diagnostic agent or a therapeutic agent, for example.Suitable classes of drugs include, for example, local anesthetics,painkillers, vasoconstrictors, antiseptics, antioxidants,anti-inflammatory agents, anti-allergens, anti-cholinergic agents,antihistamines, anti-infectives, anti-platelet agents, anti-coagulants,anti-thrombotic agents, anti-scarring agents, anti-proliferative agents,chemotherapeutic agents, anti-neoplastic agents, decongestants, healingpromoting agents and vitamins (for example, retinoic acid, vitamin A,depaxapanthenol, vitamin B and their derivatives), hypersomolar agents,immunomodulators, immunosuppressive agents, mucolytics, and combinationsand mixtures thereof.

For the treatment of nasal conditions, it may be useful for the drug tocomprise an anti-inflammatory agent, an anti-infective agent, anantihistame, a decongestant, a mucolytic agent, or combinations ormixtures thereof. For the treatment of otic conditions, it may be usefulfor the drug to comprise an anti-inflammatory agent, an anti-infectiveagent, or combinations or mixtures thereof. For the treatment of throatconditions, it may be useful for the drug to comprise a painkiller, ananti-infective agent, a chemotherapeutic agent, or combinations ormixtures thereof.

In some variations, a mucolytic agent is included in the drug coating tohelp clear the mucous layer, as previously stated. The mucolytic agentmay comprise carbocysteine, erdosteine, acetylcysteine, bromheksin,expigen syrup (sorbimacrogol laurate 300 and ammonium chloride),guaifenesin, glyceryl guaicolate, iodinated glycerol, or combinations ormixtures thereof.

Examples of antioxidants include tocopherol (vitamin E), alphatocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, citric acid monohydrate, erythorbic acid,ethyl oleate, fumaric acid, malic acid, methionine, monothioglyceraol,phosphoric acid, potassium metabisulfite, proprionic acid, propylgallate, sodium ascorbate, sodium thiosulfate, sulfur dioxide, citricacid monohydrate, tartaric acid, and thymol.

Examples of local anesthetics include ropivicaine, mepivicaine, cocaine,procaine, lidocaine, hydrocodone, oxycodone and fentanyl, morphine.Examples of vasoconstrictors include epinephrine, levonordefrin, andadrenaline.

Anti-infective agents generally include antibacterial agents, antifungalagents, antiparasitic agents, antiviral agents, antiseptics, iodine(e.g., povidone-iodine), potassium sorbate, sorbic acid, thimersol,thymol, butylene glycol, coconut oil, and vanillin. Anti-inflammatoryagents generally include steroidal and nonsteroidal anti-inflammatoryagents.

Examples of anti-allergic agents that may suitable for use with thedescribed methods and devices include, but are not limited to,pemirolast potassium (ALAMAST®, Santen, Inc.), and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof. Examples of antiproliferative agents include, butare not limited to, sirolimus, everolimus, temsirolimus, actinomycin D,actinomycin IV, actinomycin I1, actinomycin X1, actinomycin C1, anddactinomycin (COSMEGEN®, Merck & Co., Inc.). Examples of antiplatelet,anticoagulant, antifibrin, and antithrombin agents include, but are notlimited to, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibodies, recombinant hirudin, and thrombininhibitors (ANGIOMAX®, Biogen, Inc.), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof. Examples of pro-healing agents include, but are not limited to,vitamin A.

Examples of cytostatic or antiproliferative agents that may be suitablefor uses with the described methods and devices include, but are notlimited to, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril (CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.),cilazapril or lisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.);calcium channel blockers such as nifedipine; colchicines; fibroblastgrowth factor (FGF) antagonists, fish oil (omega 3-fatty acid);histamine antagonists; lovastatin (MEVACOR®, Merck & Co., Inc.);monoclonal antibodies including, but not limited to, antibodies specificfor Platelet-Derived Growth Factor (PDGF) receptors; nitroprusside;phosphodiesterase inhibitors; prostaglandin inhibitors; suramin;serotonin blockers; steroids; thioprotease inhibitors; PDGF antagonistsincluding, but not limited to, triazolopyrimidine; and nitric oxide, andany prodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Examples of antibacterial agents that may be suitable for use with thedescribed methods and devices include, but are not limited to,aminoglycosides, amphenicols, ansamycins, betalactams, β-lactams such aspenicillins, lincosamides, macrolides, nitrofurans, quinolones,sulfonamides, sulfones, tetracyclines, vancomycin, and any of theirderivatives, or combinations thereof. Examples of penicillins that maybe suitable for use with the described methods and devices include, butare not limited to, amdinocillin, amdinocillin pivoxil, amoxicillin,ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin,lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillinsodium, oxacillin, penamecillin, penethamate hydriodide, penicillin Gbenethamine, penicillin G benzathine, penicillin G benzhydrylamine,penicillin G calcium, penicillin G hydrabamine, penicillin G potassium,penicillin G procaine, penicillin N, penicillin O, penicillin V,penicillin V benzathine, penicillin V hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin, propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,and ticarcillin. In one variation, the antibacterial agent comprisesciprofloxacin. In another variation, the antibacterial agent comprisesamoxicillin.

Examples of antifungal agents suitable for use with the describedmethods and devices include, but are not limited to, allylamines,imidazoles, polyenes, thiocarbamates, triazoles, and any of theirderivatives. Antiparasitic agents that may be employed include, but arenot limited to, atovaquone, clindamycin, dapsone, iodoquinol,metronidazole, pentamidine, primaquine, pyrimethamine, sulfadiazine,trimethoprim/sulfamethoxazole, trimetrexate, and combinations thereof.

Examples of antiviral agents suitable for use with the described methodsand devices include, but are not limited to, acyclovir, famciclovir,valacyclovir, edoxudine, ganciclovir, foscamet, cidovir (vistide),vitrasert, formivirsen, HPMPA(9-(3-hydroxy-2-phosphonomethoxypropyl)adenine), PMEA(9-(2-phosphonomethoxyethyl)adenine), HPMPG(9-(3-Hydroxy-2-(Phosphonomethoxy)propyl)guanine), PMEG(9-[2-(phosphonomethoxy)ethyl]guanine), HPMPC(1-(2-phosphonomethoxy-3-hydroxypropyl)-cytosine), ribavirin, EICAR(5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamine), pyrazofurin(3-[beta-D-ribofuranosyl]-4-hydroxypyrazole-5-carboxamine),3-Deazaguanine, GR-92938X(1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide), LY253963(1,3,4-thiadiazol-2-yl-cyanamide), RD3-0028(1,4-dihydro-2,3-Benzodithiin), CL387626(4,4′-bis[4,6-d][3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazin-2-ylamino-biphenyl-2-,2′-disulfonicacid disodium salt), BABIM (Bis[5-Amidino-2-benzimidazoly-1]-methane),NIH351, and combinations thereof.

Examples of antiseptic agents suitable for use with the describedmethods and devices include, but are not limited to, alcohol,chlorhexidrine, iodine, triclosan, hexachlorophene, and silver-basedagents, for example, silver chloride, silver oxide, and silvernanoparticles.

Anti-inflammatory agents may include steroidal and nonsteroidalanti-inflammatory agents. Examples of suitable steroidalanti-inflammatory agents include, but are not limited to,21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, any of their derivatives, and combinations thereof. Insome variations, a corticosteroid is used in the sinuses and otherbodily structures described herein to prevent or reduce inflammationpost-surgery. The corticosteroid will generally be one with highpotency, high binding to glucocorticoid receptors, and lowbioavailability. For example, in some variations the corticosteroidcomprises mometasone furoate, or a pharmaceutically acceptable salt,solvate, hydrate, ester, free base, enantiomer, racemate, polymorph,amorphous, or crystal form thereof. In other variations, thecorticosteroid comprises dexamethasone, or a pharmaceutically acceptablesalt, solvate, hydrate, ester, free base, enantiomer, racemate,polymorph, amorphous, or crystal form thereof.

Examples of suitable nonsteroidal anti-inflammatory agents include, butare not limited to, COX inhibitors. These COX inhibitors may includeCOX-1 or COX nonspecific inhibitors such as, for example, salicylic acidand derivatives, aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine;para-aminophenol derivatives such as acetaminophen; indole and indeneacetic acids such as indomethacin and sulindac; heteroaryl acetic acidssuch as tolmetin, dicofenac and ketorolac; arylpropionic acids such asibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin;anthranilic acids (fenamates) such as mefenamic acid and meloxicam;enolic acids such as the oxicams (piroxicam, meloxicam) and alkanonessuch as nabumetone. The COX inhibitors may also include selective COX-2inhibitors such as, for example, diaryl-substituted furanones such asrofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole aceticacids such as etodolac and sulfonanilides such as nimesulide).

Examples of chemotherapeutic/antineoplastic agents that may be used inthe devices described here include, but are not limited to antitumoragents (e.g., cancer chemotherapeutic agents, biological responsemodifiers, vascularization inhibitors, hormone receptor blockers,cryotherapeutic agents or other agents that destroy or inhibit neoplasiaor tumorigenesis) such as alkylating agents or other agents whichdirectly kill cancer cells by attacking their DNA (e.g.,cyclophosphamide, isophosphamide), nitrosoureas or other agents whichkill cancer cells by inhibiting changes necessary for cellular DNArepair (e.g., carmustine (BCNU) and lomustine (CCNU)), antimetabolitesor other agents that block cancer cell growth by interfering withcertain cell functions, usually DNA synthesis (e.g., 6-mercaptopurineand 5-fluorouracil (5FU), antitumor antibiotics and other compounds thatact by binding or intercalating DNA and preventing RNA synthesis (e.g.,doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C andbleomycin), plant (vinca) alkaloids and other anti-tumor agents derivedfrom plants (e.g., vincristine and vinblastine), steroid hormones,hormone inhibitors, hormone receptor antagonists and other agents whichaffect the growth of hormone-responsive cancers (e.g., tamoxifen,herceptin, aromatase ingibitors such as aminoglutethamide andformestane, trriazole inhibitors such as letrozole and anastrazole,steroidal inhibitors such as exemestane), antiangiogenic proteins, smallmolecules, gene therapies and/or other agents that inhibit angiogenesisor vascularization of tumors (e.g., meth-1, meth-2, thalidomide),bevacizumab (Avastin), squalamine, endostatin, angiostatin, Angiozyme,AE-941 (Neovastat), CC-5013 (Revimid), medi-522 (Vitaxin),2-methoxyestradiol (2ME2, Panzem), carboxyamidotriazole (CAI),combretastatin A4 prodrug (CA4P), SU6668, SU11248, BMS-275291, COL-3,EMD 121974, IMC-1C11, IM862, TNP-470, celecoxib (Celebrex), rofecoxib(Vioxx), interferon alpha, interleukin-12 (IL-12) or any of thecompounds identified in Science Vol. 289, Pages 1197-1201 (Aug. 17,2000), which is expressly incorporated herein by reference, biologicalresponse modifiers (e.g., interferon, bacillus calmette-guerin (BCG),monoclonal antibodies, interleukin 2, granulocyte colony stimulatingfactor (GCSF), etc.), PGDF receptor antagonists, herceptin,asparaginase, busulphan, carboplatin, cisplatin, carmustine,cchlorambucil, cytarabine, dacarbazine, etoposide, flucarbazine,flurouracil, gemcitabine, hydroxyurea, ifosphamide, irinotecan,lomustine, melphalan, mercaptopurine, methotrexate, thioguanine,thiotepa, tomudex, topotecan, treosulfan, vinblastine, vincristine,mitoazitrone, oxaliplatin, procarbazine, streptocin, taxol orpaclitaxel, taxotere, azathioprine, docetaxel analogs/congeners,derivatives of such compounds, and combinations thereof.

Examples of decongestants that may be used in the devices and methodsdescribed here include, but are not limited to, epinephrine,pseudoephedrine, oxymetazoline, phenylephrine, tetrahydrozolidine, andxylometazoline. Examples of mucolytics that may be used in the devicesand methods described here include, but are not limited to,acetylcysteine, dornase alpha, and guaifenesin. Anti-histamines such asazelastine, diphenhydramine, and loratidine may also be used in themethods and devices described herein.

Suitable hyperosmolar agents that may be used in the devices describedhere include, but are not limited to, furosemide, sodium chloride gel,and other salt preparations that draw water from tissue or substancesthat directly or indirectly change the osmolarity of the mucous layer.

Other bioactive agents useful in the present invention include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; everolimus; tacrolimus;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs such as those described in U.S. Pat. No. 6,329,386;estradiol; clobetasol; idoxifen; tazarotene; alpha-interferon; hostcells including, but not limited to prokaryotes and eukaryotes such as,for example, epithelial cells and genetically engineered epithelialcells; dexamethasone; botulinum toxin and other neurotoxins; and, anyprodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Examples of free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, freeradical (TEMPOL), 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxymethyl sulfate, free radical; 16-doxyl-stearic acid, free radical;superoxide dismutase mimic (SODm) and any analogs, homologues,congeners, derivatives, salts and combinations thereof. Nitric oxidedonors include, but are not limited to, S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazeniumdiolates such as spermine diazenium diolate, and any analogs,homologues, congeners, derivatives, salts and combinations thereof.

The selection of drugs, the timing of delivery, and the overall amountof drug or drugs released may be determined by the intended treatmentplan, and may be further fine-tuned to meet the specific needs of anindividual patient. Components of the drug coating can be altered toadjust the release rates of the drug and/or the transfer rate of thecoating to tissue. The drug coating may be formulated so that at least25%, at least 40%, at least 50%, at least 60% at least 70%, at least80%, or at least 90% of the coating is transferred to tissue uponexpansion of the expandable device. In one variation, at least 80% ofthe drug coating is transferred. The desired amount of transfer can beaccomplished with one or multiple expansions of the expandable device.Furthermore, when multiple expansions are performed with a singledevice, the drug coating can be formulated to be partially transferredwith each expansion. This may be useful when a single device is to beused to treat multiple sites, e.g., multiple sinuses. In somevariations, the drug coating can be formulated so that transfer of thedrug coating is linear with each expansion, e.g., with each ballooninflation. For example, 25% of the coating can be transferred with thefirst inflation, another 25% can be transferred with the secondinflation, another 25% transferred with the third inflation, and theremaining 25% transferred with the fourth inflation. In othervariations, the drug coating can be formulated to have a first ordertype of transfer where, e.g., 60% of the coating is transferred with thefirst inflation, 20% of the coating is transferred with the secondinflation, 10% is transferred with the third inflation, and 5% istransferred with the fourth inflation. In further variations, the drugcoating is provided in multiple layers on the expandable device. In thisvariation, one layer is transferred with each expansion. Accordingly,the number of layers will generally correspond to the number ofexpansions intended to be employed. In some cases, a primer coatingwithout drug can be incorporated between each drug layer.

Additionally or alternatively, the surface of the expandable device canbe treated prior to coating in a manner that enhances transfer of thedrug coating or slows transfer of the drug coating during expansion. Forexample, when the surface of an inflatable balloon is plasma treated orcoated with a primer coating(s), certain parameters of the treatment canbe altered to manipulate transfer rates.

The dose of drug delivered (e.g., mometasone furoate) when the drugcoating is transferred may range from about 0.5 mg to about 3 mg. Forexample, the dose of drug transferred may be about 0.5 mg, about 1.0 mg,about 1.5 mg, about 2.0 mg, about 2.5 mg, or about 3.0 mg. In somevariations, the dose transferred ranges from about 0.5 mg to about 1.5mg. In other variations, the dose transferred is more than 3.0 mg. Thedose density (i.e., the amount of drug per balloon working lengthsurface area) in the coating (of, e.g., mometasone furoate) may also beadjusted to vary the amount of drug delivered to tissue, and may rangefrom about 100 μg/cm² to about 600 μg/cm². For example, the dose densitymay be 100 μg/cm²′ 200 μg/cm², 300 μg/cm², 400 μg/cm², 500 μg/cm², or600 μg/cm².

The coating may include any suitable number or combination of drugs andexcipients, depending on the condition to be treated, desired rate ofdrug release and coating transfer, etc. The coating may include one,two, three, four, or five drugs, or more than five drugs. When two drugsare included in the coating formulation, they can be mometasone furoateand an antihistamine, or mometasone furoate and an antibacterial agent.Likewise, the coating may include one, two, three, four, or fiveexcipients, or more than five excipients. When the tissue to be treatedincludes mucociliary tissue, it may be beneficial for the drug coatingto include one or more penetration enhancing, mucoadhesive, or mucolyticexcipients, as previously stated. For example, the drug coating caninclude mometasone furoate as the drug, polysorbate as the penetrationenhancer, polyacrylic acid as the mucoadhesive, and acetylcysteine asthe mucolytic. The drug coating may comprise a drug to excipient ratioranging from about 3:1 to about 1:3.

In one variation, the drug coating formulation comprises acorticosteroid and a mucoadhesive excipient. In another variation, thedrug coating formulation comprises a corticosteroid and a mucolyticexcipient. In yet a further variation, the drug coating formulationcomprises a corticosteroid and a penetration enhancer as the excipient.The drug coating formulation may also include a corticosteroid, amucoadhesive excipient, and a mucolytic excipient; or a corticosteroid,a mucoadhesive excipient, a mucolytic excipient, and a penetrationenhancer. The corticosteroid in the aforementioned drug coatings can bemometasone furoate. Other drug coating formulations may include anantibacterial agent in combination with one or more of a mucoadhesiveexcipient, a mucolytic excipient, and a penetration enhancer. In someinstances, the mucolytic may be the active drug instead of the excipientin the drug coating.

The drug coating formulation may comprise mometasone furoate as theactive agent, and as excipients, poly(vinyl pyrrolidone) and polysorbate80. This drug coating variation may be useful in treating a nasalcondition, e.g., rhinitis, sinusitis, or mucosal inflammation. Otherdrug coatings for treating nasal conditions may include mometasonefuroate, poly(vinyl pyrrolidone), polysorbate 80, and poly(ethyleneglycol). Alternatively, the drug coatings for treating a nasal conditionmay include mometasone furoate as the active agent, and as excipients,poly(ethylene glycol) and polysorbate 80. In further variations, thedrug coatings for treating a nasal condition may include mometasonefuroate as the active agent, and as excipients, poly(vinyl pyrrolidone)and propylene glycol. Other excipient combinations that may be includedwith mometasone furoate as the active agent are: poly(vinyl pyrrolidone)and polysorbate 80; poly(ethylene glycol) and propylene glycol; andpoly(ethylene glycol) and glycerol caproate. In some variations, thecoating for treating a nasal condition comprises an antibacterial as theactive agent, e.g., amoxicillin, and polysorbate 80 as the excipient. Inother variations, the coating for treating a nasal condition comprisesan antibacterial as the active agent, e.g., amoxicillin, and poly(vinylpyrrolidone) as the excipient. In yet further variations, the coatingfor treating a nasal condition comprises an antibacterial as the activeagent, e.g., amoxicillin, and poly(ethylene glycol) as the excipient.Alternatively, the coating for treating nasal conditions may include anantibacterial as the active agent, e.g., amoxicillin, and a combinationof polysorbate 80, poly(vinyl pyrrolidone), and poly(ethylene glycol) asexcipients. When the nasal condition involves treating the inferiorturbinate, the drug coating may be layered onto a non-compliantspherical balloon having a diameter of, e.g., 15 mm to about 50 mm, andthe balloon inflated for a time period of about 5 seconds. When thenasal condition involves treating one or more the sinus ostia, the drugcoating may be placed on a cylindrical balloon (either compliant,non-compliant, or semi-compliant) having a diameter of, e.g., about 4 mmto about 6 mm, and a length of about 10 mm to about 25 mm. Here theballoon may also be inflated for a time period of about 5 seconds toabout 5 minutes. A single balloon can be inflated multiple times at thesame of different target tissue site (e.g., the inferior turbinate orone or more sinus ostia), as previously stated.

When an otic condition is to be treated, the drug coating formulationmay include an antibacterial agent, an anti-inflammatory agent, e.g., acorticosteroid such as dexamethasone, or combinations thereof, inaddition to an excipient or combination of excipients. For example, theantibacterial agent may comprise ciprofloxacin or amoxicillin, and theexcipient may comprise a polysorbate, poly(vinyl pyrrolidone), orpoly(ethylene glycol). In one variation, the drug coating formulationcomprises ciprofloxacin as the antibacterial, and polysorbate 80 as theexcipient. In another variation, the drug coating formulation comprisesciprofloxacin as the antibacterial, and poly(vinyl pyrrolidone) as theexcipient. In yet further variations, the drug coating formulationcomprises ciprofloxacin as the antibacterial agent, and poly(ethyleneglycol) as the excipient. In some instances, it may useful for the drugcoating formulation to include ciprofloxacin and polysorbate 80,poly(vinyl pryrrolidone), and poly(ethylene glycol) as excipients. Whenthe otic condition involves treating the external ear or Eustachiantube, the drug coating may be layered onto a cylindrical compliantballoon having dimensions of, e.g., 3 mm diameter×20 mm length. Here theballoon may be inflated for a time period of about 5 seconds to about 5minutes. In some instances, a coated non-compliant or semi-compliantballoon may be useful in treating otic conditions.

When a throat condition is to be treated, the drug coating formulationmay include as the active agent, a painkiller, an anesthetic, ananti-inflammatory agent, e.g., a corticosteroid, and combinationsthereof. Here the drug coating may be provided on a compliant,non-compliant, or semi-compliant balloon depending on the specificthroat condition being treated, and the balloon inflated for about 5seconds to about 5 minutes. For example, if the balloon is to be used totreat esophageal stenosis, a compliant balloon may be selected andinflated multiple times for about 5 seconds. Other exemplary drugcoating formulations are provided below in Table 1. It is understoodthat the combinations listed above or in Table 1 are not exclusive orlimiting, and that any suitable drug(s) and excipient(s) for the desiredindication may be used in the coating formulations.

TABLE 1 Drug D:E Formulation (D) Excipient(s) (E) Ratio  1 MF*Polysorbate 1:1  2 MF* Polysorbate 1:1.3  3 MF* Polysorbate 1:2  4 MF*Poly(ethylene glycol) 1:1.3  5 MF* Poly(ethylene glycol) 1:2  6 MF*Poly(ethylene glycol):Polysorbate 1:1:0.05  7 MF* Poly(ethyleneglycol):Polysorbate 1:2:0.05  8 MF* Poly(vinyl pyrrolidone):propyleneglycol 1:1:0.2  9 MF* Poly(vinyl pyrrolidone):propylene glycol 1:2:0.210 MF* Poly(vinyl pyrrolidone):polysorbate 1:1:0.03 11 MF* Poly(vinylpyrrolidone):polysorbate 1:2:0.03 12 MF* Poly(ethylene glycol):Propyleneglycol 1:1:0.1 13 MF* Poly(ethylene glycol):glycerol caproate 1:1:0.1 14MF* Poly(ethylene glycol):glycerol caproate 1:2:0.1 *Mometasone FuroateDelivery Device

The expandable devices described here may be delivered using anysuitable delivery device. The delivery device may be configured todeliver the expandable device and may be used to move the expandabledevice into an expanded configuration. The expandable device may beloaded into the delivery device in the low-profile configuration,deployed from the delivery device at the treatment site, and thenexpanded (e.g., inflated, in instances when the expandable device is aninflatable structure) to the expanded configuration. Deploying theexpandable device may comprise distally advancing the expandable devicebeyond the distal end of the delivery device. Alternatively, deployingthe expandable device may comprise maintaining the expandable device atthe desired location while proximally retracting the delivery device.Various ports, e.g., for irrigation and/or advancing viewing or imagingelements may also be included in the delivery device.

In some variations, the delivery device may comprise a short stiffcatheter, for example, where a therapeutic treatment is being performedin the nasal passageways or sinus cavities where the distance from thepoint of insertion to the treatment site is relatively short. Otherdelivery devices may include a malleable tip, e.g., with a bending anglerange of up to about 135 degrees, to aid in optimizing access to thefrontal, sphenoid, or maxillary sinuses. In some other variations, thedelivery device may comprise a small guiding catheter. For example, invariations in which the expandable device is delivered to the Eustachiantube, the delivery device may be configured to navigate to thecartilaginous part of the tube and may comprise a small guiding catheterthat is sized and configured to avoid the bony part of the tube and thelocation of several critical arteries so as not to disrupt them. Infurther variations, the expandable device is delivered to the targettissue site over a guidewire.

In some variations, the systems described here may comprise a sheathconfigured to cover the expandable device. The sheath may be used as analternative to or in addition to a delivery catheter. The catheterand/or sheath may protect the drug coating from scraping off before orduring delivery, keep the drug coating dry until deployment, and/ormaintain the expandable member in the low-profile configuration. Thesheath may be used with a non-compliant expandable device to return thedevice to a low-profile configuration, such that pleating or refoldingof the non-compliant expandable device is not necessary post coating.Instead of a sheath, a topcoat could be layered onto the drug coating toprotect it until deployment, as previously stated.

In some variations, the sheath may be elastic and may be expanded to beinstalled on and around the expandable device without moving ordisrupting the drug coating, as described below. The sheath may bescored, perforated or otherwise configured to be removed from theexpandable member once the expandable member is at the treatment site.

After the expandable device is inflated and the drug is transferred fromthe expandable device to the tissue, in some variations, the deliverydevice may also be used to remove the expandable device from thetreatment site. In some variations, the inflation fluid may be removedfrom the expandable member in order to deflate the expandable member toa low-profile configuration. The delivery device may receive thedeflated expandable member for removal by distally advancing thecatheter over the expandable member, or proximally retracting theexpandable member.

Methods

The expandable devices described here may be delivered to any suitableportion of the anatomy in any suitable manner. As mentioned above, theexpandable devices may be used for the treatment of certain conditionsor diseases of the nose, ear, and throat, wherein it is desirable tomaintain a therapeutic level of a locally delivered drug for a desiredperiod of time. As previously described, in some variations, theexpandable device may be delivered to a sinus cavity, sinus ostium,paranasal sinus, ethmoid sinus, inferior turbinate, middle turbinate,osteomeatal complex, and/or nasal cavity. The method may be for treatingnasal conditions such as post-surgical inflammation, rhinosinusitis,and/or allergic rhinitis, for example. In other variations, theexpandable device may be delivered to the Eustachian tube, external earcanal, and/or inner ear. The method may be for treating otic conditionssuch as post-surgical inflammation, otitis media, Meniere's disease,and/or tinnitus. In yet other variations, the expandable device may bedelivered to the throat for the treatment of post-surgical pain, such astonsillectomy pain, or for oncology (e.g., esophageal cancer), airwaystenosis, chronic laryngitis, or epiglottitis.

Generally, the expandable devices may be delivered in a minimallyinvasive fashion. In these instances, the expandable devices may bedelivered in a low-profile configuration. The expandable devices may bepreloaded in or on a delivery device, but need not be. Generally, atleast a portion of the delivery device may be introduced into the body.In some variations, the delivery device may be introduced into a naturalopening in the body, such as a nostril. In other variations, thedelivery device may be introduced into an opening formed in the body viaone or more procedures (e.g., a surgically-formed opening). In some ofthese variations, the artificially-created opening may be pre-formedusing one or more tools that are separate from the delivery device. Insome variations, one or more portions of the delivery device may be usedto create the opening. In other variations, one or more portions of theexpandable device may be used to create the opening.

Once the delivery device is introduced into the body, at least a portionof the delivery device may then be advanced to a target location. Insome variations, this advancement may occur under direct visualization.The direct visualization may be achieved by a device external to thedelivery device, such as an endoscope, or it may be achieved by one ormore visualization devices separate from the delivery device, or it maybe achieved by one or more visualization devices attached to thedelivery device or disposed within one or more portions (i.e., a lumenof a cannula) of the delivery device. In some variations,electromagnetic localizer elements may be included on the expandabledevice or delivery device to enable navigation by an electromagnetictracking technology. Additionally or alternatively, the advancement mayoccur under indirect visualization, such as fluoroscopy, ultrasound, orcomputer image guidance. In other variations, the delivery device mayinclude an optical fiber that illuminates the position of the devicewith respect to the target tissue or area to be treated (e.g., a sinus).The illumination may be visible from outside the patient. In furthervariations, such as in some instances of delivery to the middleturbinate, the expandable device may be delivered without direct orindirect visualization.

After the expandable device is delivered to the target location, theexpandable device may be expanded into an expanded configuration. Invariations where the expandable device is expandable in response to oneor more forces or stimuli, one or more appropriate forces of stimuli maybe applied to the expandable device to expand the expandable device intoan expanded configuration. For example, when the expandable device is aninflatable structure (e.g., a balloon), the inflatable structure may beexpanded into an expanded configuration by delivery of a liquid or gasto the interior of the inflatable structure. In variations in which theexpandable device is compliant, the expandable device may distend withinflation to the expanded configuration. In other variations, e.g., whenthe expandable device is pleated, folded, or wrapped to assume alow-profile configuration, upon inflation, the expandable device mayunfurl to expand to the expanded configuration. In yet other variations,the expandable device may both distend with inflation and unfurl withinflation, for example, when the expandable device is semi-compliant.The expanded device in its expanded configuration may be shaped as shownin FIGS. 1A-1L. It is understood that other shapes may be employed thatare tailored to the specific anatomy to be treated.

The expandable device may be expanded one or multiple times to transferthe drug coating, dilation of tissues, or both. Once expanded, theexpandable device may be configured to conform at least partly to theshape of the bodily structure and substantially contact the bodilystructure. For example, the expandable device may conform to the sinusor nasal cavity and substantially contact the sinus or nasal cavitywall. The percentage of surface area of the expandable device in contactwith the cavity wall may be sufficient to transfer the drug coating andprovide the appropriate delivery of one or more drugs to the tissue. Forexample, about 10% to about 100%, about 20% to about 100%, about 30% toabout 100%, about 40% to about 100%, about 50% to about 100%, about 60%to about 100%, about 70% to about 100%, about 80% to about 100%, orabout 90% to about 100% of the surface area of the expandable device maybe in contact with the sinus or nasal cavity wall. In some instances,the expansion of the expandable device may act to anchor the expandabledevice against or into tissue. In other instances, it may be useful tocontrol the direction of expansion to target a particular area fortreatment. Directional expansion may be achieved using a directionalballoon (e.g., as shown in FIGS. 1F and 1L), or by including as part ofthe delivery system, a rotatable sheath with an opening or cut-out thatis capable of exposing only the intended surface area of the expandabledevice for targeted expansion and tissue contact, or for directionallyanchoring the expandable device against the tissue for increasedcontact.

As mentioned above, the pressure of the expandable device when expandedmay be sufficient for maintaining contact of the surface against thesinus or nasal mucosa, or other bodily structure described herein, butnot cause unwanted damage or reshaping. For example, when the expandabledevice is a compliant balloon, the inflation pressure of the compliantballoon may be between about 2 atm and 16 atm, more specifically betweenabout 4 atm and 6 atm.

The expandable device may be left in place for any suitable amount oftime. It may be desirable for the expandable device to be left in placefor a sufficient period to transfer the drug coating and deliver one ormore drugs to the tissue. As previously described, the drug coating maybe formulated with a high drug-to-excipient ratio to enhance fastrelease from the expandable device during a short time period ofinflation. Expansion times (e.g., inflation times) ranging from underone minute to multiple hours may be utilized for ear and nasalapplications for enhanced drug uptake. For example, in some variationsthe expandable device may be left in place (expanded) for about 5seconds to about 2 hours, about 30 seconds to about 2 hours, about 5minutes to about 1 hour, about 30 seconds to 5 minutes, about 5 secondsto about 5 minutes, or about 10 minutes to about 30 minutes. In somevariations, the expandable device and/or drug coating is structured sothat a physician can control the amount of coating (and thus, drug)delivered by controlling the expansion time (e.g., inflation time). Inother words, the amount of drug delivered can be based on the durationof expansion at the one or multiple tissue sites, e.g., one or moreparanasal sinuses. In another variation, the expandable device is leftin place for about 5 seconds. A shorter expansion time may result inoverall less mucosal injury and thus may be beneficial when drugdelivery to multiple sinuses or target sites is to be performed. In somevariations, the entire procedure may be performed during a single doctoroffice visit. In other variations, where the expandable device is to beleft expanded and in place for longer periods of time (e.g., 1-2 hours),the expandable device may comprise a pressure valve that the patient mayrelease him/herself outside of the doctor's office.

In further variations, multiple expansion-collapse cycles (e.g.,inflation-deflation cycles) of the same expandable device could be usedto release multiple coating layers to a single or multiple tissue sites.Each inflation-deflation cycle could be of the same or differentduration. A single expandable device may also be repeatedly expanded totreat multiple/different sinuses. For example, a single expandabledevice may be used to treat two to eight sinuses. Specifically a singleexpandable device may be used to treat two sinuses, three sinuses, foursinuses, five sinuses, six sinuses, seven sinuses, or eight sinuses. Inone variation, a single expandable device may be used to treat twofrontal sinuses and two maxillary sinuses and/or two sphenoid sinuses.In other variations, multiple expansions can be used to transfer drugacross inferior and middle turbinates.

Upon transference of the drug coating from the expandable device to thetissue, the delivery device and expandable device may be removed. Priorto removal, the expandable device may be collapsed or otherwise returnedto a low-profile configuration. As described above, in variations inwhich the expandable device comprises an inflatable device, theinflation fluid may be withdrawn from the expandable device and theexpandable device deflated to the low-profile configuration. Whenmultiple inflations are to be performed, the inflatable device may beconfigured to rapidly deflate or collapse back to its pleated/foldedstate to prevent loss of the remaining drug. The delivery device maythen be used to receive the expandable device and the expandable deviceand delivery device removed from the body, or the expandable device maybe removed without the use of the delivery device, or using a separatedevice.

After the drug and/or coating are transferred to the tissue, it may beeluted gradually over time. For example, the formulation may beconfigured for sustained release of drug at a therapeutic level for aperiod of days, weeks, or months. In some variations, a therapeuticlevel of drug delivery may be provided for up to 5 days, up to 14 days,up to 30 days, up to 45 days, up to 60 days, up to 75 days, or up to 90days, depending on the specific treatment application. In othervariations, the treatment time may range from about 2 months to about 3months. For example, when the method is intended for treatment ofallergic rhinitis applications, it may be desirable to maintain atherapeutic level of drug for the duration of an allergy season (e.g.,about 2 months to about 3 months). When a drug is to be delivered afterfunctional endoscopic sinus surgery (FESS), the formulation may beconfigured to release the drug over a period of about 14 to 28 days.When a drug is to be delivered after balloon sinuplasty alone, theformulation may be configured to release the drug over a period of about7 to 14 days.

In some instances, the method of treatment may comprise multiple roundsof treatment. For example, patients who suffer from chronic conditions,such as otitis media, or who experience more than one allergy season(e.g., due to different allergens) each year, may get multipletreatments during the year. This may provide continuous therapeutictreatment in healing the condition and/or sustained relief from thesymptoms associated with the condition.

For applications where long-term mechanical support is desirable, themethods described herein may be combined with an implantable device. Forexample, the methods described herein may be combined with the placementof a scaffold or stent. In some variations, the scaffold or stent may bedrug eluting. In some variations the scaffold or stent may be expandable(e.g., balloon expandable or self-expanding). In some variations, thescaffold or stent may be bioresorbable (e.g., comprise a bioresorbablesynthetic biopolymer), but need not be.

When the methods described herein are combined with an implantabledevice, the expandable devices described herein may be used to deliver adrug before implantation of the implant, or may be usedpost-implantation of the implant. In variations in which the expandabledevice is used first, the device may help pre-dilate the ostia forimproved ease of delivery and implantation of the implant. In variationsin which the expandable device is used second, the device may helppost-dilate the implant for improved apposition. In addition to helpingdeliver an effective localized dose of a drug, when combined with ascaffold or stent, the methods described here may, for example, maintainthe patency of the sinus cavities, and help prevent obstruction causedby adhesions between healing or inflamed mucosal surfaces.

Manufacturing

The devices described herein may be made in any suitable manner. Ingeneral, molds may be used to form expandable devices designed forspecific anatomies, and the materials selected for the expandable devicemay be based on desired compliance for the specific application.

Drugs may be coated on the expandable member when fully inflated,partially inflated, or folded. Coating an inflated expandable device maymaximize drug delivery and tissue coverage. In some variations where theexpandable device is folded, the drugs may be coated on the certainregions of the expandable device that become protected upon folding ofthe expandable device. This may help to protect the coating duringdelivery or loading into a delivery device or sheath. Pleat geometrysuch as pleat number, length, and shape can be adjusted for the desiredamount of drug coverage during refold. Tight refolding to a low profilemay be beneficial in keeping drug loss during delivery but prior toinflation at less than about 10%. This selective coating may be achievedby masking of the region that is desired to be non-coated. In othervariations, drugs may be coated on a portion of the expandable devicebased on a desired treatment area within the target cavity. For example,an expandable device intended for use in the nasal cavity may be coatedon one side to deliver drug to the turbinates, but uncoated on a secondside to minimize drug delivery to the nasal septa (e.g., to prevent anydeterioration of the septa). An expandable device to be used at multipletreatment sites and/or expanded multiple times may be provided with amulti-layered coating.

In some variations, the drug coating may be patterned on the expandabledevice or provided on specific areas of the expandable device, dependingon, e.g., the anatomy or particular target tissue site to be treated.For example, the pattern could include solid or dashed lines of the drugcoating, the drug coating dotted on the expandable device, or the drugcoating provided as a spiral around the expandable device, etc. Thethickness of the drug coating may range from about 10 μm to about 500μm. In some variations, the thickness of the drug coating can be varied,e.g., structured to be thicker on some areas of the expandable devicethan others.

Drug coating may be achieved by methods such as spray coating, pipetteor syringe coating, or dip coating. Spray coating may achieve improvedtissue uptake and drug delivery uniformity. Spray coating may providehomogenous distribution of the drug in the coating. For improved coatingadhesion, the expandable device may be cleaned with a solvent and driedprior to coating. In addition, plasma treatment with an inert gas, suchas argon or oxygen, after cleaning may increase the cleaning andwettability of the expandable device surface leading to increasedcoating adhesion and release of the coating upon contact with mucus atthe mucosal tissue site. One or more parameters of the plasma treatmentcan be altered to adjust drug release to the desired rate. For example,power, flow rate of the inert gas, cycle time, and number of cycles canbe manipulated to adjust the rate of drug release. Table 2 provides alist of exemplary parameters for plasma treatment. In some variations,the expandable device may be primed with a hydrophilic excipient toenhance drug release. In other variations, the expandable device may beprimed with a hydrophobic (lipophilic) excipient to slow drug release.The hydrophilic to lipophilic properties of the excipient are selectedfor either a faster or slower release rate. The priming can be performedalone or in addition to cleaning and plasma treatment.

TABLE 2 Exemplary Parameters for Plasma Treatment Oxygen Argon Plasma RFPower Flow Rate Flow Rate Time/ # of (watts) (cc/min) (cc/min) Cycle(min) Cycles 100 0 40 5 3 100 20 20 10 2 100 40 0 15 1 100 10 30 10 3125 15 25 7 2 150 20 20 5 1 175 25 15 3 3 200 30 10 1 2 300 15 0 1 1 1000 15 20 1

After coating of the expandable device, e.g., a balloon, the expandabledevice may be re-folded at an elevated temperature, e.g., at about 50degrees Celsius, about 60 degrees Celsius, about 70 degrees Celsius, orabout 80 degrees Celsius, and for about 5 minutes, about 30 minutes, orabout one hour, to achieve a low profile. In some variations, theballoon may be re-folded under vacuum at a reduced pressure andtemperature while applying vacuum to its interior volume to obtain a lowprofile. Re-folding of the expandable device can be followed bysheathing, packaging in a foil pouch with argon, nitrogen or other inertgas, and sterilization using gamma irradiation or electron beams.

In some variations, the manufacturing method may include cleaning theballoon surface and/or treating the balloon with plasma, inflating theballoon, spray coating the balloon with a drug coating formulation,drying the balloon coating at room temperature or elevated temperature,and re-folding the balloon as described above.

In other variations, the manufacturing method may include cleaning theballoon surface and/or treating the balloon with plasma, inflating theballoon, spray coating the balloon with a drug coating formulation,exposing the coated balloon to a solvent vapor (solvent vaporannealing), and re-folding the balloon as described above. Thesemanufacturing processes are outlined in FIG. 2. Suitable solvent vaporsmay include, but are not limited to, water, acetone, methanol, ethanol,2-propanol, 1-propanol, linear alcohols, methane, ethane, propane,butane, pentane hexane, cyclohexane, heptane, methyl iso-butyl ketone,methyl ethyl ketone, dimethylsulfoxide, dimethylacetamide,dimethylformamide, formamide, methyl acetate, ethyl acetate, propylacetate, isopropyl acetate, n-butyl acetate, dimethyl ether, diethylether, dipropyl ether, N-methylpyrrolidone, dichloromethane, chloroform,difluoromethane, fluoroform, freons, benzene, toluene, xylene, blendsthereof, and combinations thereof. The preferred vapor can depend on anumber of variables such as the compositions of the coatings andsurfaces of the expandable device. In further variations, themanufacturing method includes drying the balloon coating at roomtemperature and exposing the coated balloon to a solvent vapor.

The drying conditions and/or exposure to solvent vapor may affect drugmorphology in the coating. For example, the particular solvent vaporused, duration of solvent vapor exposure, and/or drying rate (e.g.,slower drying) during coating and post-coating may be used to controlthe crystallinity of the drug. The ability to control drug morphologymay be useful since crystalline drug forms typically exhibit greaterresidence times in tissue, and may be beneficial when a longer period ofdrug delivery is desired. In variations where shorter periods of drugdelivery are needed, faster drying, shorter exposure to solvent vapor,or a particular solvent vapor may be used to provide more amorphous drugin the coating. Thus, in some instances the manufacturing methods can betailored to provide a coating that includes a crystalline form of thedrug. In other instances, the manufacturing methods can be tailored toprovide a coating that includes the amorphous form of a drug. In yetfurther instances, the manufacturing methods can be tailored to providea coating having a mixture of crystalline and amorphous forms of a drug.For example, the manufacturing methods can be manipulated to provide acoating including about 100% amorphous drug, about 5% to about 10% ofcrystalline drug (and about 90% to about 95% amorphous drug), about 20%to about 25% crystalline drug (and about 75% to about 80% amorphousdrug), about 50% crystalline drug (and about 50% amorphous drug), orgreater than about 50% crystalline drug (less than 50% amorphous drug).For the treatment of nasal or mucosal conditions, it may be useful forthe coating to provide mometasone furoate in crystalline or amorphousforms, or a combination of crystalline and amorphous forms. In somevariations, about 25% to about 75% of the mometasone furoate is providedin crystalline form in the drug coating.

In addition to the particular components of the coating formulation, themanufacturing methods described herein may help minimize drug lossduring delivery to the treatment site and maximize drug delivery uponinflation and contact with tissue.

EXAMPLES Example 1: Manufacture of an Expandable Device with an AirDried Drug Coating

A 30 mm compliant 80 A Pellethane® balloon was cleaned with 70%isopropanol and air dried. The balloon was then treated with oxygenplasma and later spray coated with a mometasone furoate formulationlisted in Table 1. The coating was allowed to dry at room temperatureovernight. Post-spray pass drying was completed using nitrogen gas. Theballoon was then re-folded and heat set using a custom pleating machine.The coated balloon was sheathed and packaged under nitrogen gas andsterilized by electron beam irradiation.

Example 2: Drug Loss and Release from Air Dried Drug Coating in an OvineModel

A drug coated balloon made using the process described in Example 1 wasadvanced through a sheep nostril using a rigid 4 mm endoscope to theinferior turbinate, expanded for 5 minutes, and then deflated andremoved from the nostril. Follow-up studies found that less than 10%drug loss occurred prior to inflation. The drug coating remaining on thenon-inflated balloon tracked to the nasal passage and removed wasdissolved in acetonitrile and the amount of drug quantified by HLPC. Inthis study, more than about 80% of drug was released after 5 minutes ofinflation.

Example 3: Manufacture of an Expandable Device with a Drug CoatingExposed to Solvent Vapor

A 30 mm 80 A Pellethane® compliant balloon was cleaned with 70%isopropanol and dried in an oven. The balloon was then treated withoxygen plasma and immediately spray coated with a mometasone furoateformulation listed in Table 1. Post-spray pass drying was conducted withnitrogen gas. Next, the drug coated balloon was treated by solvent vaporannealing (i.e., exposed to a solvent vapor) in a sealed chambersaturated with ethanol for four hours at room temperature. After solventvapor annealing, the balloon was re-folded and heat set using a custompleating machine. The coated balloon was then sheathed and packagedunder nitrogen gas and sterilized by electron beam irradiation.

Example 4: Drug Uptake and Plasma Concentration of Drug Coating Exposedto Solvent Vapor in an Ovine Model

A drug coated balloon made using the process described in Example 3 wasadvanced to a sheep maxillary sinus using a rigid 4 mm endoscope andexpanded for 5 minutes, and then deflated and removed from the nostril.After 7 days the animal was sacrificed and tissue samples obtained fromthe maxillary sinus and surrounding tissues. HPLC studies conducted onthe tissue samples found that the maxillary sinus tissue had amometasone furoate concentration of 146 ng/g (nanograms of drug per gramof tissue), and that tissues surrounding the maxillary sinus had amometasone furoate concentration of 55 ng/g, proving that an efficaciouslevel of drug was achieved. Plasma concentration of mometasone furoatewas also measured over 7 days. Referring to Table 3 below and FIG. 3,mometasone furoate (MF) plasma concentration was low and found todecrease over the 7 day period from an initially low value. This studydemonstrated that high local tissue (sinus tissue) concentrations ofdrug can be achieved with the drug coated balloons while minimizing therisk of systemic exposure. Low systemic exposure generally lowers therisk of a patient experiencing side effects from the delivered drug.

TABLE 3 MF Plasma Concentration Days (ng/mL) 0 0.3 1 0.3 4 0.05 7 <10.01

Example 5: Increasing Drug Crystallinity Using Solvent Vapor Annealing

A 30 mm 10 A ChronoPrene® compliant balloon was cleaned with 70%isopropanol and air dried. The balloon was then treated with oxygenplasma and immediately spray coated with a mometasone furoateformulation listed in Table 1. Post-spray pass drying was conducted withnitrogen gas. Next, the drug coated balloon was treated by solvent vaporannealing (i.e., exposed to a solvent vapor) in a sealed chambersaturated with ethanol for two hours at room temperature. Microscopicexamination of the drug coating before and after solvent vapor annealingfound increased crystallinity of the mometasone furoate after exposureto the ethanol vapor. The coated balloon were then sheathed and packagedunder nitrogen gas and sterilized by electron beam irradiation.

Although the foregoing invention has, for the purposes of clarity andunderstanding been described in some detail by way of illustration andexample, it will be apparent that certain changes and modifications maybe practiced, and are intended to fall within the scope of the appendedclaims.

What is claimed as new and desired to be protected by Letters Patent ofthe United States is:
 1. A system for delivering treatment to a nasal,otic, or throat tissue site, comprising: an expandable device having alow-profile configuration and an expanded configuration, and having adrug coating on an external surface thereof; a delivery device having asheath, the expandable device disposed within the sheath in thelow-profile configuration until deployment at one or more target tissuesites; and an inflation source in fluid communication with theexpandable device, configured to expand the expandable device one ormore times, where expansion of the expandable device transfers a portionof the drug coating from the external surface of the expandable deviceto the one or more target tissue sites, and where transfer of the drugcoating maintains a therapeutic level of local drug delivery.
 2. Thesystem of claim 1, wherein the inflation source is configured to delivera fluid or a gas to an interior of the expandable device and therebyexpand the expandable device, and wherein the inflation source isfurther configured to withdraw the fluid or gas from the interior of theexpandable device and thereby collapse the expandable device.
 3. Thesystem of claim 1, wherein the drug coating comprises at least one of alocal anesthetic, painkiller, vasoconstrictor, antiseptic, antioxidant,anti-inflammatory agent, anti-allergen agent, anti-cholinergic agent,antihistamine, anti-infective agent, anti-platelet agent,anti-coagulant, anti-thrombotic agent, anti-scarring agent,anti-proliferative agent, chemotherapeutic agent, anti-neoplastic agent,decongestant, healing promoting agent, vitamin, hypersomolar agent,immunomodulator, immunosuppressive agent, mucolytic, or combinationthereof.
 4. The system of claim 1, wherein the drug coating comprisesmometasone furoate or pharmaceutically acceptable salts, solvates,hydrates, esters, free base, enantiomers, racemates, polymorphs,amorphous, or crystal forms thereof.
 5. The system of claim 1, whereinthe drug coating comprises a drug and one or more excipients, with adrug to excipient ratio ranging from 3:1 to 1:3.
 6. The system of claim5, wherein the excipient comprises at least one of a poly(vinylpyrrolidone), polysorbate, poly(ethylene glycol), phospholipid, fattyacid, sodium dodecyl sulfate, poloxamer,hydroxypropyl-beta-cyclodextrin, sucrose fatty acid monoester, orcombination thereof.
 7. The system of claim 1, wherein the drug coatingcomprises at least one of a chitosan, collagen, elastin, silk,silk-elastin, alginate, cellulose, dextran, polyalkoanates, hyaluronicacid, gelatin, and gellan, polylactide, poly(lactide-co-glycolide),poly(lactide-co-ε-caprolactone), polyglycolide, polyhydroxybutyrate,polyhydroxyvalerate, poly(ethylene glycol), polydioxanone, polyglactin,poly(ε-caprolactone), polyglyconate, poly(glycolide-co-trimethylenecarbonate), poly(sebacic acid), poly(ester urethane), poly(esterurethane) urea, cross-linked PEG, polyNIPAAM, PEG-PLA block copolymer,poloxamer or combination thereof.
 8. The system of claim 1, wherein thedrug in the drug coating has a dose density ranging from about 100μg/cm² to about 600 μg/cm².
 9. The system of claim 1, wherein the drugcoating has a thickness on the external surface of the expandable deviceof from about 10 μm to about 500 μm.
 10. The system of claim 1, whereinthe delivery device further comprises an optical fiber that illuminatesthe position of the device with respect to the target tissue sites. 11.The system of claim 1, wherein the expandable device is expanded atmultiple target tissue sites.
 12. The system of claim 11, wherein theexpandable device has a plurality of pleats or folds that promote returnto the low-profile configuration and prevent loss of the drug coatingafter each expansion at the multiple target tissue sites.
 13. The systemof claim 1, wherein the drug coating is patterned on the exteriorsurface of the expandable device in a configuration for anatomy specificto the at least one target tissue sites.
 14. The system of claim 1,wherein the delivery device has a malleable distal tip.
 15. The systemof claim 1, further comprising a topcoat applied on the drug coating,the topcoat being configured to dissolve upon contact with the at leastone target tissue sites.
 16. The system of claim 1, wherein the deliverydevice further comprises a guidewire, with the expandable devicearranged to move along the guidewire.
 17. A method of treating a nasal,otic, or throat condition, comprising: providing an expandable devicecomprising a drug coating on an external surface thereof and having alow-profile configuration and an expanded configuration; delivering theexpandable device in the low-profile configuration to a target tissuesite; transferring a portion of the drug coating from the externalsurface to the target tissue site by at least one expansion of theexpandable device; removing the expandable member from the target tissuesite; and maintaining a therapeutic level of local drug delivery at thetarget tissue site from the transferred drug coating for a time periodeffective to treat the target tissue site.
 18. The method of claim 17,wherein the expandable device is expanded at multiple target tissuesites, and wherein transfer of drug coating to each target tissue siteis by at least one expansion of the expandable device at each targettissue site.
 19. The method of claim 17, wherein transfer of drugcoating delivers about 0.5 mg to about 3.0 mg of the drug to the targettissue site.
 20. The method of claim 17, wherein the nasal condition isselected from the group consisting of post-surgical inflammation,turbinate hypertrophy, rhinosinusitis, and rhinitis.
 21. The method ofclaim 17, wherein the target tissue site is a maxillary sinus, a frontalsinus, an ethmoidal sinus, a sphenoidal sinus, a sinus ostium, aninferior turbinate, a middle turbinate, a superior turbinate, a nasalcavity, the osteomeatal complex, the nasopharynx, adenoid tissue, or acombination thereof.
 22. The method of claim 17, wherein the oticcondition is selected from the group consisting of post-surgicalinflammation, otitis media, Meniere's disease, Eustachian tubedysfunction, and tinnitus, and wherein the target tissue site is theEustachian tube, external ear canal, or middle ear.
 23. The method ofclaim 17, wherein the throat condition is selected from the groupconsisting of post-surgical pain, esophageal cancer, airway stenosis,chronic laryngitis, tonsillitis, and epiglottitis.
 24. The method ofclaim 17, wherein the expandable device is an inflatable balloon thatdistends upon inflation to the expanded configuration at an inflationpressure between about 2 atm and 16 atm.
 25. The method of claim 17,wherein each expansion of the expandable device is a time period of fromabout 5 seconds to about 5 minutes.
 26. The method of claim 17, whereinthe time period effective to treat the target tissue site is up to 90days.
 27. The method of claim 17, wherein about 60% of the drug coatingis transferred to the target tissue site upon expansion of theexpandable device.
 28. The method of claim 17, wherein about 40% of thedrug coating is transferred to the target tissue site upon expansion ofthe expandable device.
 29. The method of claim 17, wherein about 25% ofthe drug coating is transferred to the target tissue site upon expansionof the expandable device.
 30. The method of claim 17, wherein about 20%of the drug coating is transferred to the target tissue site uponexpansion of the expandable device.